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Ubiquitous ubiquitination

DII small banner By Warren R. Heymann, MD
June 28, 2017

epidermolysis bullosa simplex
Generalized severe epidermolysis bullosa simplex. Blister classification. Single blisters were defined as a count of 1. Blister nests derived from 1 healing blister were defined as a count of 1. Redness without convexes was not counted. Only time points for which good quality photographs were available (good resolution, clear visualization of blisters) were included in the final evaluations. Blisters were counted in the context of the whole treatment to distinguish between active and healing blisters.
Credit: JAAD

While perusing the Journal of Investigative Dermatology, I was intrigued by the theory that a variant of epidermolysis bullosa simplex (EBS) may be due to “dysregulation of autoubiquitination” caused by mutations in KLHL24 (Kelch-like family member 24) (1). Just saying that phrase gave me the sense that my IQ had raised 50 points. Unfortunately, not understanding it brought that inflated score back to baseline (if not lower). What does “dysregulation of autoubiquitination” mean?

Ubiquitination regulates the function and signaling of a profusion of proteins in various cellular pathways. Ubiquitination serves as a degradation mechanism of proteins as part of the ubiquitin-proteasome pathway, but is also involved in additional cellular processes such as activation of the NFκB inflammatory response and DNA damage repair. Ubiquitin (Ub) is a highly conserved 76-amino acid protein expressed in all cell types that can be polymerized into various linkages. The resulting linkage of Ub chains creates a certain topology that can be sampled by interacting proteins thereby dictating the fate of the substrate. Ubiquitination is a conserved multistep process that begins with the activation of ubiquitin with ATP by the E1 ubiquitin-activating enzyme. Ultimately, deubiquitinating enzymes (DUBs) remove ubiquitin from target substrates and recycle ubiquitin into the cytosolic pool. (2)
According to Ma et al: “dysregulated deubiquitination can lead to improper protein localization and protein–protein interactions, intracellular metabolic disorder, accumulation of misfolded proteins, amplification of inflammatory response, as well as aberrant activation of enzymes and signaling pathways, which are detrimental to the cellular homeostasis and greatly involve in the pathogenesis of many diseases.” (3)

The growth of knowledge of ubiquitination in promoting signal amplification, novel protein interactions, and protein turnover has been exponential. This is particularly important in understanding how DNA double-stranded breaks (DSBs) are repaired, with many components of the ubiquitin (Ub) conjugation, deconjugation, and recognition machinery now identified as key factors in DSB repair. Additionally, a member of the Ub-like family, small Ub-like modifier (SUMO), has also been recognized as integral for efficient repair, in a process called SUMOylation. (4)

In the case of EBS, the most common mutations are in keratins 5 and 14. KLHL24 is part of the family of more than 40 genes with a Kelch-like motif that forms part of a ubiquitin-ligase complex. In the article by Lee et al, the mutations resulted in the loss of the first 28 amino acids of the protein, leading to a truncated protein that was more stable than the wild-type protein. This mutant protein then promoted excessive ubiquitination and degradation of keratin 14 (so-called “dysregulation of autoubiquitination”). The EBS phenotype associated with pathogenic mutations in KLHL24, although variable, presents with marked birth trauma—especially on the lower legs, with additional early blistering often involving the trunk and upper limbs. Bullae characteristically heal rapidly with subtle atrophic scarring. Blistering persists throughout childhood, especially in response to minor trauma. Nail defects and oral ulceration are common, and transient milia also occur. With increasing age, blistering severity tends to lessen. (1)

This commentary is a rudimentary overview of ubiquitination and SUMOylation, devoid of the exquisite intricate detail that is still being deciphered. The potential for targeted therapies in this process is unlimited for many diseases, including malignancies such as melanoma. It may seem arcane, however, in the near future articles about ubiquitination and their clinical dermatologic applications will be ubiquitous.

1. Lee JYW, et al. Mutations in KLHL24 add to the molecular heterogeneity of epidermolysis bullosa simplex. J Invest Dermatol 2017; 137: 1378-80.
2. Gallo LH, et al. The importance of regulatory ubiquitination in cancer and metastasis. Cell cycle 2017; 16: 634-8.
3. Ma J, et al. Ubiquitination in melanoma pathogenesis and treatment. Cancer Med 2017. May 23 [Epub ahead of print]
4. Morris JR, Garvin AJ. SUMO in the DNA double-stranded break response: Similarities, differences, and cooperation with ubiquitin. J Mol Biol 2017; May 17 [Epub ahead of print]

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